An iPSC whole call cancer vaccine combined with radiotherapy (RT) improved CT26 tumor control compared to GM-CSF-adjuvanted iPSCs or fibroblasts by enhancing tumor cell apoptosis and cytotoxic T cell infiltration. The inclusion of RT engaged the STING pathway, as evidenced by i.t. mRNA. To expand the range of targeted antigens to include tumor-specific antigens, neoantigen-expressing iPSCs were engineered via AAV, which improved tumor control in the CT26 and 4T1 models, promoted infiltration of CD11c+ and granzyme B+ cells, and enhanced CT26 neoantigen-specific T cell responses, all of which were further enhanced by RT combination.
Contributed by Morgan Janes
ABSTRACT: Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFN_ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.
Author Info: (1) Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 406040, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw. Translation Research Core, Chi
Author Info: (1) Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 406040, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw. Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw. Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw. (2) Department of Surgery, School of Medicine, China Medical University, Taichung, 406040, Taiwan, ROC. Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, 302, Taiwan, ROC. Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. (3) Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. (4) Innovation Frontier Institute of Research for Science and Technology, National Taipei University of Technology, Taipei, 106344, Taiwan, ROC. Department of Electrical Engineering, National Taipei University of Technology, Taipei, 106344, Taiwan, ROC. Department of Biomedical Engineering, China Medical University, Taichung, 406040, Taiwan, ROC. (5) Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. Bioinformatics and Biostatistics Core, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 10055, Taiwan, ROC. (6) Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 406040, Taiwan, ROC. Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. (7) Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. (8) Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 406040, Taiwan, ROC. (9) Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 406040, Taiwan, ROC. Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. (10) Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. d94032@mail.cmuh.org.tw. Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. d94032@mail.cmuh.org.tw. Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 406040, Taiwan, ROC. d94032@mail.cmuh.org.tw. (11) Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. d18047@mail.cmuh.org.tw. School of Chinese Medicine and Graduate Institute of Chinese Medicine, China Medical University, Taichung, 406040, Taiwan, ROC. d18047@mail.cmuh.org.tw.
